SMAD3 and p300 complex scaffolding by long non-coding RNA LIMD1-AS1 promotes TGF-β-induced breast cancer cell plasticity.

Fan C, Cats D, Selle M, Khorosjutina O, Dhanjal S, Schmierer B, Mei H, Ten Dijke P, Wang Q

Nucleic Acids Res. 53 (16) - [2025-08-27; online 2025-09-01]

Transforming growth factor (TGF)-β signaling enhances cancer cell plasticity by inducing epithelial-to-mesenchymal transition (EMT). Here, we identified a TGF-β-induced long non-coding RNA, LIMD1 Antisense RNA 1 (LIMD1-AS1) that strengthens the SMAD-mediated transcriptional response to TGF-β. LIMD1-AS1 expression is upregulated in breast cancer tissues compared to normal breast tissues, and high LIMD1-AS1 expression is associated with poor prognosis in breast cancer patients. Depletion of LIMD1-AS1 hinders TGF-β-induced EMT, migration, and extravasation of breast cancer cells. Mechanistically, LIMD1-AS1 promotes the interaction between SMAD3 and its transcriptional coactivator p300, thereby enhancing SMAD3 transcriptional activity and TGF-β/SMAD signaling. We demonstrated that LIMD1-AS1 binds to the MAD homology 2 (MH2) domain of SMAD3 and the interferon-binding domain (IBiD) of p300. Displacing LIMD1-AS1 from p300 by its competitor interferon regulatory factor 3 (IRF3) suppressed the effects of LIMD1-AS1 on potentiating TGF-β/SMAD signaling. Furthermore, blockage of p300 acetyltransferase activity with a pharmacological inhibitor A-485 reduced the ability of LIMD1-AS1 to enhance SMAD3 transcriptional activity, TGF-β-induced EMT, and migration. This study identifies LIMD1-AS1 as a novel stimulator of TGF-β signaling by establishing a positive feedback loop and highlights its potential as a therapeutic target for breast cancer.

CRISPR Functional Genomics [Service]

PubMed 40889156

DOI 10.1093/nar/gkaf841

Crossref 10.1093/nar/gkaf841

pmc: PMC12400928
pii: 8245226